Efficacy assessment of novel methanimine derivatives in chronic constriction injury-induced neuropathic model: An in-vivo, ex-vivo and In-Silico approach.

The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4­chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4­chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.

Assessment of ubiquitin specific Peptidase-18 gene in peripheral blood of chronic hepatitis C patients treated with direct-acting antiviral drugs.

Hepatitis C virus (HCV) infection remains one of the leading causes of liver complications globally. Ubiquitin Specific Peptidase-18 (USP18) is a ubiquitin-specific protease that cleaves interferon-stimulated gene 15 (ISG15) from ISGylated protein complexes and is involved in regulating interferon responsiveness. To study the effect of direct-acting antivirals (DAAs) on the USP18 gene using qPCR, 132 participants were recruited and classified into different groups based on treatment duration. USP18 expression was raised compared to rapid virologic response (RVR) and early virologic response (EVR) groups with P = 0.0026 and P = 0.0016, respectively. USP18 was found to be 7.36 folds higher in naïve patients than those with RVR and sustained viral response (SVR). In RVR and SVR groups where patients had cleared HCV RNA after treatment with direct-acting antiviral agents (DAA) therapy, the expression of USP18 was found to be low, with a fold change of 1.3 and 1.4 folds, respectively. Expression of USP18 was significantly higher in the non-RVR group than in the RVR group. In the No EVR group, gene expression was significantly higher than in the EVR group. It is concluded that targeting HCV proteins using DAAs can cause USP18 expression to be normalized more effectively. Moreover, USP18 is a vital marker indicating treatment resistance and distinguishing responders from non-responders during DAA therapy.

Synthesis, molecular docking and DFT analysis of novel bis-Schiff base derivatives with thiobarbituric acid for α-glucosidase inhibition assessment.

A library of novel bis-Schiff base derivatives based on thiobarbituric acid has been effectively synthesized by multi-step reactions as part of our ongoing pursuit of novel anti-diabetic agents. All these derivatives were subjected to in vitro α-glucosidase inhibitory potential testing after structural confirmation by modern spectroscopic techniques. Among them, compound 8 (IC50 = 0.10 ± 0.05 µM), and 9 (IC50 = 0.13 ± 0.03 µM) exhibited promising inhibitory activity better than the standard drug acarbose (IC50 = 0.27 ± 0.04 µM). Similarly, derivatives (5, 6, 7, 10 and 4) showed significant to good inhibitory activity in the range of IC50 values from 0.32 ± 0.03 to 0.52 ± 0.02 µM. These derivatives were docked with the target protein to elucidate their binding affinities and key interactions, providing additional insights into their inhibitory mechanisms. The chemical nature of these compounds were reveal by performing the density functional theory (DFT) calculation using hybrid B3LYP functional with 6-311++G(d,p) basis set. The presence of intramolecular H-bonding was explored by DFT-d3 and reduced density gradient (RGD) analysis. Furthermore, various reactivity parameters were explored by performing TD-DFT at CAM-B3LYP/6-311++G(d,p) method.

Triazolothiadiazoles and Triazolothiadiazines as New and Potent Urease Inhibitors: Insights from In Vitro Assay, Kinetics Data, and In Silico Assessment.

Hyperactivity of the urease enzyme induces the pathogenesis of peptic ulcers and gastritis. The identification of new urease inhibitors can reduce the activity of urease. Therefore, in the current study, we have evaluated 28 analogues of triazolothiadiazole and triazolothiadiazine heteroaromatics for their in vitro urease inhibitory efficacy. All the tested compounds displayed a remarkable inhibitory potential ranging from 3.33 to 46.83 µM. Among them, compounds 5k and 5e emerged as lead inhibitors with IC50 values of 3.33 ± 0.11 and 3.51 ± 0.49 µM, respectively. The potent inhibitory potential of these compounds was ∼6.5-fold higher than that of the marketed drug thiourea (IC50 = 22.45 ± 0.30 µM). The mechanistic insights from kinetics experiments of the highest potent inhibitors (4g, 5e, and 5k) revealed a competitive type of inhibition with ki values 2.25 ± 0.0028, 3.11 ± 0.0031, and 3.62 ± 0.0034 µM, respectively. In silico modeling was performed to investigate the binding interactions of potent inhibitors with the enzyme active site residues, which strongly supported our experimental results. Furthermore, ADME analysis also showed good druglikeness properties demonstrating the potential of these compounds to be developed as lead antiurease agents.

In Vivo and In Silico Assessment of the Cardioprotective Effect of Thymus linearis Extract against Ischemic Myocardial Injury.

Myocardial infarction is irreversible cardiac tissue necrosis due to the blockage of one of the arteries. It leads to an insufficient supply of oxygen and nutrients, creating muscular damage in the affected regions. In the present study, aqueous methanolic extract of Thymus linearis was prepared to evaluate its activity against ischemic stress due to free radical production. GC-MS analysis was performed to evaluate the phytochemicals present in the plant extract. A chemical database of 30 compounds was virtually screened against NF-κB, COX2, and MCL, where γ-cadinene, ß-bisabolene, and ß-caryophyllene were found to be the best interacting ligands. To systematically assess cardioprotective activity against ischemia, isoproterenol and doxorubicin were used to induce cardiotoxicity in rats. The prepared extract of T. linearis (100 mg/kg) was given daily to animals for 21 days before injecting isoproterenol (85 mg/kg of animal weight) subcutaneously in two doses on the 20th and 21st days. In the case of doxorubicin, cardiotoxicity was induced in rats by a single injection (15 mg/kg) on the seventh day, and the extract was given to animals for 10 consecutive days. Animals' blood samples were used to monitor cardiac, liver, and other marker enzymes, including LDH, CPK, and AST. Superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were also assayed in blood plasma to determine the degree of oxidative stress. H&E staining was performed to evaluate cardioprotection by plant extract, showing significant preventive effects in reducing cardiac injury induced by isoproterenol and doxorubicin.

Synthesis, Bioactivity Assessment, and Molecular Docking of Non-sulfonamide Benzimidazole-Derived N-Acylhydrazone Scaffolds as Carbonic Anhydrase-II Inhibitors.

This research reports the synthesis of new benzimidazole-derived N-acylhydrazones (NAH), their characterization using various spectroscopic methods, and in vitro evaluation as potent carbonic anhydrase-II inhibitors. Among the target compounds (9-29), few showed higher inhibition than the standard acetazolamide (IC50: 18.6 ± 0.43 µM), for example, compound 9 (IC50: 13.3 ± 1.25 µM), 10 (IC50: 17.2 ± 1.24 µM), 12 (IC50: 14.6 ± 0.62 µM), and 15 (IC50: 14.5 ± 1.05 µM). Molecular docking was performed on the most active compounds, which revealed their binding interactions with the active site of the enzyme, thus supporting the experimental findings.

Fabrication and Biological Assessment of Antidiabetic α-Mangostin Loaded Nanosponges: In Vitro, In Vivo, and In Silico Studies.

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic ß-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively.

A Framework for Maternal Physical Activities and Health Monitoring Using Wearable Sensors.

We propose a physical activity recognition and monitoring framework based on wearable sensors during maternity. A physical activity can either create or prevent health issues during a given stage of pregnancy depending on its intensity. Thus, it becomes very important to provide continuous feedback by recognizing a physical activity and its intensity. However, such continuous monitoring is very challenging during the whole period of maternity. In addition, maintaining a record of each physical activity, and the time for which it was performed, is also a non-trivial task. We aim at such problems by first recognizing a physical activity via the data of wearable sensors that are put on various parts of body. We avoid the use of smartphones for such task due to the inconvenience caused by wearing it for activities such as "eating". In our proposed framework, a module worn on body consists of three sensors: a 3-axis accelerometer, 3-axis gyroscope, and temperature sensor. The time-series data from these sensors are sent to a Raspberry-PI via Bluetooth Low Energy (BLE). Various statistical measures (features) of this data are then calculated and represented in features vectors. These feature vectors are then used to train a supervised machine learning algorithm called classifier for the recognition of physical activity from the sensors data. Based on such recognition, the proposed framework sends a message to the care-taker in case of unfavorable situation. We evaluated a number of well-known classifiers on various features developed from overlapped and non-overlapped window size of time-series data. Our novel dataset consists of 10 physical activities performed by 61 subjects at various stages of maternity. On the current dataset, we achieve the highest recognition rate of 89% which is encouraging for a monitoring and feedback system.

Assessment of DNA damage induced by endosulfan in grass carp (Ctenopharyngodon idella Valenciennes, 1844).

Endosulfan is an organochlorine pesticide, which is commonly used throughout the world. It accumulates in the environment and may cause significant damage to the ecosystems, particularly to the aquatic environments. The present study was conducted to evaluate the genotoxic effect of endosulfan on the grass carp (Ctenopharyngodon idella) blood. The fish were exposed to three different concentrations, 0.75 ppb/day, 1.0 ppb/day, and 1.5ppb/day of endosulfan for 7, 14, 21, and 28 days. The study was a randomized control trial and the control group was not exposed to endosulfan. The results showed that after 7 days, the level of DNA damage in all the concentrations was significant (P < 0.05), while after 14, 21, and 28 days' trials, highly significant (P < 0.000) level of DNA damage was observed. Hence, time- and dose-dependent DNA damage was observed in fish DNA by comet assay. It is concluded from our results that with the increase in endosulfan concentration and exposure duration, the level of DNA damage also increased. As the current study showed the severe genotoxic effect of endosulfan in Ctenopharyngodon idella, therefore, the imprudent and indiscriminate use of endosulfan should be controlled and monitored by the concerned government authorities.

Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis.

Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC50 values of 8.93 ±â€¯0.21 and 6.88 ±â€¯0.42 µM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.

Force Resistance Training in Hand Grasp and Arm Therapy: Feasibility of a Low-Cost Videogame Controller.

OBJECTIVE: To design and evaluate a low-cost gaming station that supports force resistance training in pediatric arm/hand grasp therapies through mainstream videogame play. METHODS: The gaming station was developed through an iterative participatory design process and includes a force feedback game controller (Novint Falcon), custom grips, arm/wrist supports, and software to interface with mainstream games and manage difficulty settings in the controller. The station was tested for usability and feasibility with six therapists and six children with cerebral palsy, 7-16 years of age, attending weekly therapy sessions over 12 weeks. Pre- and post-assessments of perceived performance and satisfaction on self-identified goals were measured on the Canadian Occupational Performance Measure (COPM). RESULTS: The gaming station was considered highly usable by therapists with a score of 76.7 (standard deviation [SD] = 6.1) on the System Usability Scale. Overall, children enjoyed the games, achieved high repetition rates for wrist extensions and arm movements, and all made clinically significant progress on therapy goals. Increases of 3.13 (SD = 1.69) on the performance scale and 2.97 (SD = 0.98) on the satisfaction scale were reported on the COPM. Conclusiion: In-clinic force resistance training for development of upper limb functional capacities is feasible using low-cost video game components adapted to therapy through a participatory design process.

Diospyros, an under-utilized, multi-purpose plant genus: A review.

The genus Diospyros from family Ebenaceae has versatile uses including edible fruits, valuable timber, and ornamental uses. The plant parts of numerous species have been in use as remedies in various folk healing practices, which include therapy for hemorrhage, incontinence, insomnia, hiccough, diarrhea etc. Phytochemical constituents such as terpenoids, ursanes, lupanes, polyphenols, tannins, hydrocarbons, and lipids, benzopyrones, naphthoquinones, oleananes, and taraxeranes have been isolated from different species of this genus. The biological activities of these plants such as antioxidant, anti-inflammatory, analgesic, antipyretic, anti-diabetic, antibacterial, anthelmintic, antihypertensive, cosmeceutical, enzyme-inhibitory etc. have been validated by means of an in vitro, in vivo, and clinical tests. As a rich reserve of pharmacologically important components, this genus can accelerate the pace of drug discovery. Accordingly, the aim of the present review is to survey and summarize the recent literature pertaining to the medicinal and pharmacological uses of Diospyros, and to select experimental evidence on the pharmacological properties of this genus. In addition, the review also aims at identifying areas that need development to make use of this genus, especially its fruit and phytochemicals as means for economic development and for drug discovery.

Lead Assessment in Biological Samples of Children with Different Gastrointestinal Disorders.

Lead (Pb) levels have been evaluated in the biological samples of children with different gastrointestinal disorders. Blood, scalp hair, and urine samples of children (of age 4-10 years) complaining about different gastrointestinal disorders were analyzed. For comparison, age matched healthy subjects were also included in this study. Biological samples were digested in a microwave oven prior to Pb determination by graphite furnace atomic absorption spectrometry. Significant differences in Pb profile were found between the diseased and referent children. Elevated Pb contents were observed in case of diseased children than WHO permissible limit, while normal results were obtained for healthy referents. The results were compared with those of healthy children having the same age, socioeconomic status, and residential areas.